This proposal describes a five-year training program to develop an academic career in Hematology/Oncology and gene therapy. The program will further advance the investigator's research in the development of viral vector strategies for the treatment of HIV. The investigator will be mentored by Dr. David Russell, well recognized for his achievements in developing viral vector systems. The treatment of advanced HIV infection has been complicated by the continuing appearance of drug resistance strains. There are limited treatment options available to individuals infected with HIV resistant to multiple classes of drugs. Aggressive therapeutic options, including gene therapy, are appropriate for these individuals. A major limitation of clinical gene therapy trials has been poor gene transfer into hematopoietic stem cells (HSCs). Dr. Russell's laboratory has demonstrated efficient gene transfer rates into HSCs, using retroviral vectors based on foamy virus (FV). There are clear advantages for using FV vectors for gene therapy to treat HIV infection. These advantages include: 1) wild-type FV infection is non-pathogenic in all animal hosts, 2) FV vectors efficiently transduce human HSCs, and 3) unlike lentiviral vectors, FV vectors can target critical HIV proteins, such as Rev, without reduction in titer. The objectives of this proposal are to develop FV vectors containing anti-HIV gene strategies and to perform preclinical assessment of the vector's ability to transduce and protect differentiated human CD34 cells from wild-type HIV infection. The specific aims of the proposal include: 1) Create and test foamy viral vectors containing a transdominant inhibitor Rev protein; 2) Develop FV vectors that combine different strategies that block HIV; and 3) Add a drug selection element to the combination anti-HIV FV vectors and demonstrate in vivo selection in a murine model. The completion of this project and the training received at the University of Washington will prepare the principle investigator to be a leading researcher in gene therapy.